Reattempt of tyrosine kinase inhibitor discontinuation after maintenance therapy with ponatinib in patients with chronic myeloid leukemia in the chronic phase

JRCT ID: jRCTs041190117

Registered date:17/02/2020

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: chronic myeloid leukemia in chronic phase
• Date of first enrollment: 10/03/2020
• Target sample size: 45
• Study type: Interventional
• Intervention(s): Single-arm study in patients with CML-CP who have failed to attain a successful treatment-free remission after TKI discontinuation (defined as loss of MMR or DMR) and regained a DMR (defined as MR4.5 [less than 0.0032%] according to the International Scale). After study registration and complete screening procedures, current TKI treatment is switched to 15 mg of ponatinib. Patients who completed ponatinib therapy for 12 months (formally 52 to 58 weeks) without loss of MR4.5 can enter the treatment-free remission phase and are observed for 24 months. The trigger for TKI retreatment (either 15 mg of ponatinib or the same dose of TKI that was used before study enrollment can be selected) is defined as a loss of MMR. Patients who required retreatment with TKI are followed up to 6 months or until the achievement of MMR.

Outcome(s)

• Primary Outcome: MMR rate at 12 months of ponatinib discontinuation

Secondary Outcome

MMR/MR4.5 rate at 24 months of ponatinib discontinuation
MR4.5 rate at 12 months of ponatinib discontinuation
Completion rate and the adverse events of ponatinib maintenance therapy for 12 months
Adverse events during retreatment with ponatinib
Cumulative MMR rate by 6 months in patients who started retreatment with TKI
Correlation between ponatinib pharmacologic concentration and treatment-free remission rate
Correlation between T/NK cell profiling (regulatory T cells, CD4/CD8 ratio, and effector T cells, etc.) and treatment-free remission rate
Correlation between serum proteome profiling (mainly cytokines) and treatment-free remission rate
Correlations between risk stratification at diagnosis of CML (Sokal or EUTOS score), TKI treatment duration, MMR/DMR duration, or the depth of molecular response and treatment-free remission rate
Correlation between peripheral endothelial cell profiling and adverse events during ponatinib therapy
Correlation between patients' backgrounds and adverse events

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1) Major BCR-ABL1 positive CML-CP
2) Aged 18 years or older
3) Less than or equal to 2 of performance status by ECOG
4) Patients who have failed to attain a successful treatment-free remission after TKI discontinuation in a formal clinical study or in clinical practice (the latter case includes only those who fulfilled conditions both TKI therapy over 3 years and MR4.5 over 2 years)
5) Patients who achieved MR4.5 after retreatment with TKI other than ponatinib
6) Patients who can visit the hospital on scheduled days
7) With written informed consent for the clinical trial (the protector's signature is required in those aged less than 20 years old)

Exclude criteria

1) Prior history of accelerated or blastic phase
2) Prior history of hematopoietic stem cell transplantation
3) With following organ dysfunction
(1) T-Bil >3 x ULN (excluding Gilbert syndrome)
(2) AST or ALT >5 x ULN
(3) Cr >3 x ULN or eGFR <30 mL/min/1.73m2
(4) Lipase or amylase >2 x ULN
(5) Heart failure within 6 months
(6) Transient ischemic attack within 6 months
(7) Acute pancreatitis within 1 year
(8) Uncontrolled or life-threatening arrhythmia
(9) QTc >470 ms on ECG
4) Poor adherence to TKI
5) Pregnant women or women who are expected to be pregnant during this study
6) With hepatitis B virus infection (positive for HBs-Ag or HBV-DNA PCR)
7) Major surgery within 28 days before study registration
8) With a diagnosis of alcohol dependence
9) With uncontrolled or active malignant disease
10) Prior history of the vascular event (regardless of arterial or venous disease)
11) With the following risk factor for thrombosis (regardless of medication)
(1) Uncontrolled hypertension (dBP >90 mm Hg or sBP >140 mm Hg)
(2) Uncontrolled dyslipidemia (TG >450 mg/dL or LDL >160 mg/dL)
(3) Uncontrolled diabetes mellitus (HbA1c >7.0%)
(4) Ankle-brachial pressure index of less than 0.90 or more than 1.40
12) With any reason considered to render the patient inadequate for the protocol therapy

Related Information

• Primary Sponsor: Iriyama Noriyoshi